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Previous studies have mainly explained disease progression from the perspectives of lymphatic injury and tissue remodeling, while local metabolic dysfunction and the associated immune alterations remain insufficiently defined. Recent evidence indicates that lymphedematous tissues exhibit disturbances in both energy metabolism and lipid metabolism. These metabolic changes can impair the survival, proliferation, and reparative capacity of lymphatic endothelial cells and may also promote inflammation, adipose deposition, and fibrosis by regulating immune-cell behavior and function. This review systematically summarizes recent advances in local metabolic dysregulation in lymphedema, discusses pharmacological strategies targeting metabolic pathways and their current translational limitations, and aims to provide a conceptual framework for future studies on immunometabolic mechanisms and therapeutic interventions in secondary lymphedema.<\/jats:p>","DOI":"10.3389\/fphys.2026.1865368","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T04:19:50Z","timestamp":1784607590000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Therapeutic targeting of local metabolic dysfunction in secondary lymphedema: mechanisms and opportunities"],"prefix":"10.3389","volume":"17","author":[{"given":"Kechen","family":"Ye","sequence":"first","affiliation":[{"name":"Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingli","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junzhe","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoxiang","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuezhong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengliang","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun\u2019e","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1074\/jbc.m101521200","article-title":"Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action","volume":"277","author":"Aguirre","year":"2002","journal-title":"J. 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